X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women.
X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women.
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DOI：
10.1016/j.cell.2022.09.002
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发表时间：
2022-10-13
期刊：
影响因子：
64.5
通讯作者：
Kang, David E.
中科院分区：
文献类型：
--
作者：
Yan, Yan;Wang, Xinming;Chaput, Dale;Shin, Min-Kyoo;Koh, Yeojung;Gan, Li;Pieper, Andrew A.;Woo, Jung-A. A.;Kang, David E.
虽然女性比男性经历显著更高的tau负担和阿尔茨海默病（AD）的风险增加，但这种脆弱性的潜在机制尚未得到解释。在这里，我们通过体外和体内模型以及人类AD脑组织证明，X-连接的泛素特异性肽酶11（USP 11）通过在赖氨酸-281处起始的tau去泛素化增强病理性tau聚集。泛素的去除提供了在赖氨酸281和274处酶促tau乙酰化的途径。USP11逃脱了完全的X失活，雌性小鼠和人类都表现出比雄性更高的USP11水平。在tau蛋白病小鼠模型中遗传消除usp11优先保护雌性免于乙酰化tau蛋白积累、tau蛋白病理学和认知障碍。USP11水平也与女性而非男性的tau病理学密切相关。因此，抑制USP11介导的tau去泛素化可能提供有效的治疗机会，以保护女性免受AD和其他tau蛋白病的易感性增加。女性患阿尔茨海默病的风险明显高于男性。在这项研究中，Yan等人揭示了一种支持易感性升高的分子机制。
Although women experience significantly higher tau burden and increased risk for Alzheimer’s disease (AD) than men, the underlying mechanism for this vulnerability has not been explained. Here, we demonstrate through in vitro and in vivo models, as well as human AD brain tissue, that X-linked ubiquitin specific peptidase 11 (USP11) augments pathological tau aggregation via tau deubiquitination initiated at lysine-281. Removal of ubiquitin provides access for enzymatic tau acetylation at lysines 281 and 274. USP11 escapes complete X-inactivation, and female mice and people both exhibit higher USP11 levels than males. Genetic elimination of usp11 in a tauopathy mouse model preferentially protects females from acetylated tau accumulation, tau pathology, and cognitive impairment. USP11 levels also strongly associate positively with tau pathology in females but not males. Thus, inhibiting USP11-mediated tau deubiquitination may provide an effective therapeutic opportunity to protect women from increased vulnerability to AD and other tauopathies. The risk of developing Alzheimer’s disease for women is significantly higher than for men. In this study, Yan et al uncovers a molecular mechanism underpinning the heightened susceptibility.
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影响因子：
13.3
作者：
Fang C;Woo JA;Liu T;Zhao X;Cazzaro S;Yan Y;Matlack J;Kee T;LePochat P;Kang DE
通讯作者：
Kang DE
DOI：
10.1016/j.jbc.2021.101263
发表时间：
2021-11
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Basic M;Hertel A;Bajdzienko J;Bonn F;Tellechea M;Stolz A;Kern A;Behl C;Bremm A
通讯作者：
Bremm A
DOI：
10.1016/j.bbadis.2014.05.029
发表时间：
2014-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Flach K;Ramminger E;Hilbrich I;Arsalan-Werner A;Albrecht F;Herrmann L;Goedert M;Arendt T;Holzer M
通讯作者：
Holzer M
影响因子：
4.7
作者：
Babu, JR;Geetha, T;Wooten, MW
通讯作者：
Wooten, MW
影响因子：
2.9
作者：
BANCHER, C;GRUNDKEIQBAL, I;WISNIEWSKI, HM
通讯作者：
WISNIEWSKI, HM